Title: Is there a pharmacologic basis for combination renin axis blockade?
Abstract: Interruption of the renin axis with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) in the patient at risk of end-stage renal disease is now well established [1.Lewis E.J. Hunsicker L.G. Bain R.P. Rohde R.D. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (4783) Google Scholar, 2.Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotecive effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar, 3.Brenner B.M. Cooper M.E. De Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar, 4.The Gisen Group Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, nondiabetic nephropathy.Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar]. These same studies also show that many patients progress despite the use of an ACE inhibitor or ARB. One can argue that we have now entered a new era in which attempts to optimize renin axis blockade are being explored in the hope that more complete blockade will lead to a better therapeutic outcome. Use of an ACE inhibitor:ARB combination has received most attention [5.Andersen N.H. Mogensen C.E. Dual blockade of the renin-angiotensin system in diabetic and nondiaetic kidney disease.Curr Hypertens Rep. 2004; 6: 369-376Crossref PubMed Scopus (11) Google Scholar, 6.Codreanu I. Perico N. Remuzzi G. Dual blockade of the renin-angiotensin system: The ultimate treatment for renal protection?.J Am Soc Nephrol. 2005; 16: 34-38Crossref Scopus (24) Google Scholar, 7.Wolf G. Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications.Kidney Int. 2005; 67: 799-812Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar]. Alternatives include the use of very high doses of ARBs, the combination of an ACE inhibitor or ARB with an agent that blocks the effects of aldosterone [8.Hollenberg N.K. Aldosterone in the development and progression of renal injury.Kidney Int. 2004; 66: 1-9Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 9.Epstein M. Buckalew JR., V. Martinez F. et al.Antiproteinuric efficacy of eplerenone, enalapril, and eplerenone/enalapril combination therapy in diabetic hypertensives with microalbuminuria.Am J Hypertens. 2002; 15: 24ACrossref PubMed Google Scholar] and, most recently, the promise of renin inhibition [10.Fisher N.D.L. Hollenberg N.K. Renin inhibition: What are the therapeutic opportunities?.J Am Soc Nephrol. 2005; 15: 592-599Crossref Scopus (161) Google Scholar]. The possibility that an ACE:ARB combination might improve therapeutics was received enthusiastically by the nephrology community. Andersen and Mogensen recently reviewed the 10 combination studies reported in patients with diabetic nephropathy and the 8 combination studies in patients with nephropathy unrelated to diabetes [5.Andersen N.H. Mogensen C.E. Dual blockade of the renin-angiotensin system in diabetic and nondiaetic kidney disease.Curr Hypertens Rep. 2004; 6: 369-376Crossref PubMed Scopus (11) Google Scholar]. They reported that 5 of the 10 studies in diabetic nephropathy showed an improvement in the reduction of proteinuria with combination therapy: The others did not. A similar pattern was reported for nondiabetic nephropathy. One limitation of most of the combination studies involves the attention paid to the issue of dose. Despite its obvious importance, this issue of dose often escapes the medical community. In the ALLHAT Study, for example, which did not show the anticipated favorable influence of ACE inhibition on nephropathy, the decision was made to start treatment with 10 mg of lisinopril daily. Few of us would think that that was an adequate dose for ACE inhibition. We still do not know how many patients in that study remained on that dose. If a substantial number did, then we would have to conclude that ACE inhibitor therapy was not really tested. The issue of dose and its role in pharmacology and therapeutics has recently been reviewed by Dr. Stata Norton in an article with the piquant title “The origins of pharmacology in the sixteenth century” [11.Norton S. Reflections. The origins of pharmacology in the 16th century.Mol Interv. 2005; 5: 144-149Crossref Scopus (13) Google Scholar]. The crucial role of dose in treatment was apparently first recognized by Paracelsus almost 500 years ago. Over 300 years ago, DeMoivre reported the equations that describe the normal distribution of a variable. In 1879, Galton argued that the variation in individual responses was related to that curve of normal distribution. Shortly thereafter, Paul Ehrlich argued that there were actually two sigmoid dose-response relationships Figure 1. One dose response was for the primary therapeutic effect. The second dose response was for adverse effects of the drug. Paracelsus had come to a similar conclusion several hundred years earlier. The farther apart that these two sigmoid curves were, the better tolerated or safer the drug. In the case of ACE inhibitors, this issue is important. We quickly run into adverse effect, as we attempt to raise ACE inhibitor dose. Conversely, in the case of the ARBs, we do not seem to have identified, yet, the toxic dose. Few drugs in history have been as well tolerated. The sigmoid-shaped dose-response relationship is actually the integral of a normal distribution. From that, several things follow. The wide use of the ED50 and ID50 (the dose inducing 50% of the maximum response and the dose inducing a 50% reduction in response) follow because the 50% dose is the point at which the variance is minimal. Another feature is that the response will rise linearly over the range 16% of maximal to 84% of maximal. The inflection point in the dose-response relationship occurs at these two points. Do these relationships, typically worked out in simple systems in vitro, apply to the intact organism? More specifically, do they apply to renin axis blockade? The answer is clearly “yes.”Figure 2 displays the relation between eprosartan dose and the renal hemodynamic response in healthy subjects in balance on a low-salt diet to maximize the response [12.Price D.A. De'Oliveira J.M. Fisher N.D.L. Hollenberg N.K. Renal hemodynamic response to an angiotensin II antagonist, eprosartan, in healthy men.Hypertension. 1997; 30: 240-246Crossref PubMed Scopus (55) Google Scholar]. The threshold dose was 10 mg, which produced a small but statistically significant response Figure 2. A 50 mg dose induced a response that was below maximum but well above the ED50. With a 100 mg dose, a rise of 135 ± 20 mL/min/1.73m2 was identified near, but not at the maximum. Doubling and quadrupling the dose to 200 mg and 400 mg induced a significant trend for an increase that accrued more gradually. As an 800 mg dose was not employed, we do not know whether a maximum had been achieved. To return to the issue of ACE:ARB combinations, one could argue that an optimal approach would employ the eprosartan dose at its inflection point, 100 mg, and add an ACE inhibitor at its upper inflection point to achieve more complete blockade. The price that one pays is the increased possibility of toxicity from the use of a second drug. There are now three studies near completion of very high-dose ARB employed in patients with type 2 diabetes and proteinuria. If it should turn out that 640 mg of valsartan, or 900 mg of irbesartan, or 128 mg of candesartan—the top doses used in the three studies—are much more effective in reducing proteinuria than is the usual dose employed for blood pressure, the ACE:ARB combination will have to be assessed, once again, with the use of that high-dose ARB. A fundamental question is involved. If the ACE inhibitor is bringing to the therapeutic table something beyond renin axis blockade, perhaps via bradykinin, nitric oxide, or other pathways, then the ACE inhibitor should be considered for routine therapy. If the ACE inhibitor under those circumstances adds nothing, then the decision is clinical. Is the cost of the drug reduced by using the combination? ACE inhibitors have become inexpensive. One hopes that success in this area will induce the pharmaceutical companies involved to consider flat pricing. In this era of renin axis inhibition optimization, we will also have to learn how to combine these agents, in their appropriate dose, with an agent that blocks the effects of aldosterone. Interesting preliminary data are already available [8.Hollenberg N.K. Aldosterone in the development and progression of renal injury.Kidney Int. 2004; 66: 1-9Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 9.Epstein M. Buckalew JR., V. Martinez F. et al.Antiproteinuric efficacy of eplerenone, enalapril, and eplerenone/enalapril combination therapy in diabetic hypertensives with microalbuminuria.Am J Hypertens. 2002; 15: 24ACrossref PubMed Google Scholar], but we will have to learn how to deal with the issue of hyperkalemia. In a study still reported only in an abstract, Epsein et al [9.Epstein M. Buckalew JR., V. Martinez F. et al.Antiproteinuric efficacy of eplerenone, enalapril, and eplerenone/enalapril combination therapy in diabetic hypertensives with microalbuminuria.Am J Hypertens. 2002; 15: 24ACrossref PubMed Google Scholar] evaluated the influence on proteinuria in patients with type 2 diabetes of eplerenone alone, enalapril alone, and a combination of the two agents. The 266 patients with type 2 diabetes mellitus had mild-to-moderate hypertension and proteinuria. In that 24-week double-blind study, eplerenone decreased microalbuminuria independent of its antihypertensive activity. The renoprotective properties of eplerenone were significantly better than enalapril used alone. The reduction in albumin excretion with combination therapy, however, was significantly more effective than monotherapy with either drug. Indeed, albumin excretion was reduced by 74% (95%CI 67-79) in the combination group, a remarkable therapeutic response. Hyperkalemia was frequent. More patients were withdrawn for hyperkalemia in the combination group [13.Moskowitz D.W. From pharmacogenomics to improved patient outcomes: Angiotensin I-converting enzyme as an example.Diabetes Technol Ther. 2002; 4: 519-532Crossref PubMed Scopus (20) Google Scholar] than in the eplerenone group [6.Codreanu I. Perico N. Remuzzi G. Dual blockade of the renin-angiotensin system: The ultimate treatment for renal protection?.J Am Soc Nephrol. 2005; 16: 34-38Crossref Scopus (24) Google Scholar] or the enalapril group [2.Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotecive effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar]. Given the remarkable therapeutic effect, it is reasonable to believe that an investment in the management of hyperkalemia may prove to be useful [14.Palmer B.F. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system.N Engl J Med. 2004; 351: 585-592Crossref PubMed Scopus (443) Google Scholar]. Approaches available include a reduction in the eplerenone dose, the combination of eplerenone with potassium-wasting diuretics such as chlorthaladone, but more novel approaches exist [13.Moskowitz D.W. From pharmacogenomics to improved patient outcomes: Angiotensin I-converting enzyme as an example.Diabetes Technol Ther. 2002; 4: 519-532Crossref PubMed Scopus (20) Google Scholar]. Moskowitz has suggested the use of a mineralocorticoid (florinef) to lower serum potassium concentration in such patients, employing furosemide or another loop diuretic to prevent fluid retention. Surely, some combination of these maneuvers will help to deal with the problem of hyperkalemia. As renin inhibitors work at the rate-limiting step, and there are compelling reasons that the rate-limiting step be addressed in combination therapy [10.Fisher N.D.L. Hollenberg N.K. Renin inhibition: What are the therapeutic opportunities?.J Am Soc Nephrol. 2005; 15: 592-599Crossref Scopus (161) Google Scholar], we will also have to learn how to incorporate these possibilities into our therapeutic planning. Those of us who enjoy this area can look forward to a great deal of fun and the development of more effective treatment options in the next decade.